A. Field of the Invention
The present invention relates to the fields of oncology, molecular biology and nucleic acid biochemistry. More particularly, it concerns methods of inducing apoptosis and/or cell cycle arrest in a cancer cell or modulating inflammation in a cell by contacting the cell with agonists of TAK1-D, including short nucleic acids.
B. Description of Related Art
Since the discovery of double-stranded RNA (dsRNA) mediated post-transcriptional gene silencing in C. elegans (Fire et al., 1998) and the description of 21 nucleotide dsRNAs effective in mammalian cells (Elbashir et al., 2001), small interfering RNAs (siRNAs) have been heavily used as a tool in biomedical research. In addition, the potential in vivo application of siRNAs as gene specific agents are now widely studied (Wall and Shi, 2003). Both applications depend decisively on the specificity of the siRNA for its target mRNA. Apart from acting as micro-RNAs and down-regulating gene expression through low stringency binding to the 3′ untranslated region of mRNAs (Scacheri et al., 2004), siRNAs elicit cellular effects through binding and activating specific proteins. Currently, three such target proteins have been identified: (1) the Toll-like receptor 3 (TLR3), a receptor involved in the immune response, which activates NFκB and triggers the production of type I interferons (Alexopoulou et al., 2001); (2) dsRNA dependent protein kinase (PKR), a protein kinase activated preferentially by longer dsRNA molecules, which triggers the upregulation of interferon-inducible transcripts (Sledz et al., 2003) and inhibits protein synthesis through phosphorylation eIF-2α (de Haro et al., 1996); (3) 2′,5′-oligoadenylate synthetase, which when activated catalyzes the formation of 2′,5′-oligoadenylates that activate RNAase L, leading to cleavage of cellular RNAs (Player and Torrence, 1998). There remains, however, a need to identify new cancer targets for RNA therapy.